Therapeutic amine-resin complex composition and method of using same



3,084,099 Patented Apr. 2, 1963 3,084,099 THERAPEUTIC AMINE-RESIN CDMPLEX COMPO- SITION AND METHOD OF USING SAME Edwin E. Hays and Bola Vithal Shetty, Rochester, N.

acsignors to Wallace & Tier-nan Inc., a corporation of Delaware No Drawing. Filed Aug. 4, 1958, Set. No. 753,093

2 Claims. (Cl. 167--55) This invention relates to novel therapeutic compositions possessing superior appetite suppressive properties. The compositions of the present invention have also been found to have mood-elevating properties.

More particularly, the invention relates to pharmaceutical compositions having reduced side effects upon administration to patients, and having potent appetite suppressive properties.

It has been known heretofore that many alpha disubstituted ethane amines are active pharmaceutical compounds exhibiting vasoprcssor or vasodilator, mydriatic, sympathomimetic, and/or central stimulant properties in varying degrees. The compound alpha,alpha,dimethylphenethylamine and its preparations were first reported by Mentzer in Comptes Rendus 213-581 (1941). This compound has also been described in U.S. Patent 2,408,345 1946). The present invention, however, is particularly concerned with the preparation of compositions of dosage-unit forms of certain resin complexes of alpha di-substituted ethane amines, or their equivalent therapeutically effective salts, for oral administration for the suppression of appetite.

The therapeutic compositions of the present invention may be prepared having the selected alpha di-substituted ethane amine, or salts, as resin complexes thereof as the predominant and primary active medicament, which is supported or suspended in a solid, substantially non-toxic pharmaceutical carrier such as lactose, starch, sugar and/or dextrin, together with other inert excipients commonly used in the preparation of tablets, such as stearic acid, magnesium stearate, gelatin and/or acacia. The dosage of active medicament in each tablet of a dosageunit form of the therapeutic composition may range from 2 milligrams of the beta-phenyl-alpha-alpha-dimcthylalpha-amino-ethane (or its salts) to 150 milligrams of the therapeutically active beta-phenyl-alpha-alpha-dimethylalpha-amino-ethanc (or salts thereof), as resin complexes of such compound. Preferably, the dosage units will range from to 60 milligrams.

The alpha di-substituted ethane amines which constitute the active mcdicarncnts in the novel dosage-unit forms comprising the invention are represented by the following general formula:

11 Ltd's-1 wherein Y represents phenyl or a saturated five or six membered ring, X represents lower alkyl, aralkyl, and aryl; and pharmacologically acceptable acid addition salts thereof; and when taken together with Z represents a sulphonic acid cation exchange resin forming a resin complex with the base. The invention thus contemplates and includes compositions comprising the above compounds when absorbed upon or ionically bound with a sulphonic acid cation exchange resin in dosage form which produces a long acting effect for a period of at least 8 to 12 hours as appetite suppressants. The invention also includes novel methods for the preparation of such resin complexes. It has been found that the best results have been ob tained by the use of the resin complexes for obtaining a prolonged and sustained activity without the undesirable side effects.

Although there are set forth below certain specific examples of the invention and its application in practical use, along with certain modifications and alternatives, it should be understood that these are not intended to be exhaustive or limiting of the invention. 0n the contrary, the specific examples are set forth as illustrations to fully acquaint others skilled in the art with the invention and principles thereof and a suitable manner of its application in practical use, so that they may be enabled to modify the invention and to adapt and apply it in numerous forms.

EXAMPLE I Preparazion of I-Benzyl Isopropylamine Resin Complex 0 CH g 4} N8 -H+H N 01 A} GHaOH CH: 4: Zn dust QHOH- NO| J; HoAc CH; 4} HI CHDH- -NH: 6 red I Resin Garth -NH:

III

OH; [@cat m].s... m... 6H;

IV A. PREPARATION OF 1PHENYL-2-METHYL-2-NITRO- PROPANOL Seventy grams (3.1 gram atoms) of sodium was dissolved in 5300 cc. of anhydrous methanol. 1420.0 grams (15.9 moles) of Z-nitropropane and 1611.0 grams (15.1 moles) of benzaldehydc were added. The mixture was allowed to stand at room temperature for 24 hours. The reaction mixture was acidified with 1500 cc. of acetic acid and the methanol was distilled off under reduced pressure. The residue was dissolved in a mixture of 3 liters of ether and 3 liters of water. The ether was washed with water, 4 times with 1500 cc. of 15% sodium bisulfite and again with water. After drying, the ether was distilled off and the residue was heated at C. under vacuum for a short time. The residue was stirred with 4 liters of ligroin in an ice bath for 1-2 hours and the solid was removed by filtration, washed and dried. The crude product was recrystallized from 2 liters of heptane to give a white solid. M.P.68-70 C. Yield- 397 grams (12.8%).

B. PREPARATION OF I'PHENYL-2METHYL'2-AMINO PROPANOL Three hundred and ninety-seven grams (2.04 moles) of 1-phenyl-2-methyl-2-nitropropanol was dissolved in 1500 cc. of ethanol. 1650 cc. of acetic acid and 2050 cc. of water were added. Then 800 grams of zinc dust was added during a period. of 16 hour at such a rate that the reaction temperature stayed approximately 70 C. After the addition was completed, the reaction mixture was kept at 60-70 C. for 5% hours, diluted with 4300 cc. of water and filtered. The filtrate was washed with ether and the aqueous fraction was made alkaline with 6400 3 cc. of 40% sodium hydroxide solution. The solution was extracted with ether. The ether was washed with 40% sodium hydroxide solution, followed by water, dried and the ether distilled off. The residue was recrystallized from 3500 cc. of heptane to give a white solid. M.P. 96-99. Yield-157 grams (46.5%).

C. PREPARATION OF l-BENZYL-ISOPROPYLAMINE One hundred and twenty-four grams (0.75 mole) of l-pheny1-2-methyl-2-aminopropanol was dissolved in 320 cc. of 57% hydriodic acid and 38.0 grams of red phosphorous was added. It was stirred and refluxed for 25 hours. The reaction mixture was cooled and 1400 cc. of water was added. It was filtered and then a small amount of sodium thiosulfate was added. The solution was made alkaline with 200 cc. of 40% sodium hydroxide solution and extracted with ether. The combined extracts were washed with water, dried, and the ether was distilled off. The residue was distilled in vacuo at 0.3-0.5 mm. to give a colorless liquid. B.P.52-54 C./0.30.5 mm. Yield-73 grams (66%).

D. PREPARATION OF RESIN COMPLEX Two hundred and ten grams of Duolite -20 resin (a copolymer polystyrene type resin with a nuclear sulfonic acid functional group) was soaked for 20 minutes with stirring in 1800 cc. of deionized water. To this slurry 90 grams (0.60 mole) of l-benzyl isopropylamine was added and the reaction mass stirred for hours.

Upon completion of the reaction period, the slurry was allowed to settle and the suspension medium removed by decantation. The resin was again suspended in 1800 ml. of deionized water, stirred for minutes and allowed to settle for decantation. This was repeated twice more to insure thorough washing, the final wash being used to transfer the resin to a Biichner funnel for drying. The resin was oven dried at 60 C. for 14 hours, weighed, and assayed.

The dry weight of the resin complex was 276.3 grams. The assay was done by standard Kjeldahl total nitrogen procedure and determined to be 28.9% l-benzyl isopropylamine or 0.54 mole reacted.

EXAMPLE II Preparation of I-Benzyl-Isopropylamine Resin Complex CHI Q t CHO H- -NO (i; CHsOH 11 all:

H CH1 0 H; H@i-NH: -Resin complex A. PREPARATION OF l-PHENYL-Z-METHYIrZ-NITRO- PROPANOL Seventy grams (3.1 gram atoms) of sodium was dissolved in 5300 cc. of anhydrous methanol. 1420.0 grams (15.9 moles) of Z-nitropropane and 1611.0 grams (15.1 moles) of benzaldehyde were added. The mixture was allowed to stand at room temperature for 24 hours. The reaction mixture was acidified with 1500 cc. of acetic acid and the methanol was distilled off under reduced pressure. The residue was dissolved in a mixture of 3 liters of ether and 3 liters of water. The ether was washed with water, 4 times with 1500 cc. of 15% sodium bisulfite and again with water. After drying the ether was distilled off and the residue was heated to 100 C. under vacuum for a short time. Then the residue was stirred with four liters of ligroin in an ice bath for 12 hours and the solid was removed by filtration, washed and dried. The crude product was recrystallized from 2 liters of heptane to M.P.

B. PREPARATION OF 1PHENYL-l-CHLORO-WMETHYL- 2-NITROPROPANE Twenty grams (0.102 mole) of l-phenyl-2-methyl-2- nitropropanol was treated with an excess of thionyl chloride and one gram of anhydrous calcium chloride. Then it was heated on a steam bath for 2 hours under dry conditions. After standing overnight at room temperature, it was filtered and the residue was washed with anhydrous ether. From the combined filtrates, the ether and the excess of thionyl chloride were removed using an aspirator. The residue was distilled in vacuo at 110 C./ 0.5 mm.

C. PREPARATION OF l-BENZYL-ISOPROPYLAMINE RESIN COMPLEX Dissolve l-phenyl-1-chloro-2-methyl-2-nitropropane in absolute methanol, add the resin, the catalyst and hydrogenate. Filter and transfer the reaction mixture to sieve No. 60. Wash with cold water and dry.

EXAMPLE III Preparation of I-BenzyI-Isopropylamine Resin Complex I Na CHO HCNO: a CHIOH H CH1 ([1 (g HI N I r d P OH H A. PREPARATION OF l-PHENYL-2-METHYL-2-NITRO- PROPANOL Seventy grams (3.1 gram atoms) of sodium was dis solved in 5300 cc. of anhydrous methanol. 1420.0 grams (15.9 moles) of Z-nitropropane and 1611.0 grams (15.1 moles) of benzaldehyde were added. The mixture was allowed to stand at room temperature for 24 hours. The reaction mixture was acidified with 1500 cc. of acetic acid and the methanol was distilled oil? under reduced pressure. The residue was dissolved in a mixture of 3 liters of ether and 3 liters of water. The ether was washed with water, 4 times with 1500 cc. of 15% sodium bisulfite and again with water. After drying, the ether was distilled ofii and the residue was heated at C. under vacuum for a short time. Then the residue was stirred with four liters of ligroin in an ice bath for 1-2 hours and the solid was removed by filtration, washed and dried. The crude product was recrystallized from 2 liters of heptane to M.P. 68-70" C.

B. PREPARATION OF 2-NI'IRO-2,2-DIMETHYL1- PHENYLETHANE In a 500 cc. round bottomed flask, equipped with a stirrer and a reflux condenser, were placed 14.6 grams (0.075 mole) of l-phenyl-Zmethyl-Z-nitropropanol, 32 cc. of 57% hydriodic acid and 3.8 grams of red phosphorous. The mixture was stirred and refluxed for 25 hours. The reaction mixture was cooled and mixed with water. It was treated with sodium thiosulfate followed by sodium hydroxide solution. It was extracted with ether, dried over anhydrous sodium sulfate and filtered. From the filtrate, the ether was removed and the product was purified.

C- P E N OF iiNHI4- R BY lA ing other starting materials, other cyclo groups, such as REfiIN QMJ cyc oae ty may e b a n Dissolve 2-nitro-2,2-dimethyl-l-phenylethane in absocs ins i regardless of W P 0f catalute methanol, add the resin, the catalyst and hydrog n lysts 1S employ, method uuhzable the produc ate. Filter and transfer the reaction mixture to sieve No. of a ta-cyclo-alpha-drmethyl-ammo ethane, a 60 w with cold and dry catalyst of the former type belng chosen when the cyclo radical is m be kept as an unsaturated nucleus and the EXAMPLE Iv latter type being suitable when it is desired to saturate the 0H: ring.

5 2., I The solution during hydrogenation should not be suffi- C h clently alkaline to remove the hydrochloric acid from the amine group as that would permit the aminoethane com Resin pound to react with itself. @011;- I -i0= As generally recognized with this class of amines, they a [131 may be used either as free amines or as amine salts and OH as primary or secondary amines. a The following examples illustrate the novel composi @011? 'Resm wimp! tions of the invention in solid form.

2 EXAMPLE VI A. PREPARATION OF 2-NITRO-2,2-DIMETHYL1- 0 Table, of Hcl PHENYLETHANE Thirty-four grams of sodium was dissolved in 3000 cc. Per Tablet, Formula Per 10,000, of absolute methanol. Then 650.0 grams of 2-nitropro milligrams mm pane and 190.0 grams of ben zyl chloride were added. It

was refluxed for 8 hours. The reaction mixture was l gz igi p ogrgn lamin jaol 1,128 cooled and filtered. From the filtrate, the solvent was restarch, use. 280 mwi'd and the e d was led in vacuo. 1 k aailygg 335 V: E

B. PREPARATION or l-BENZYL-ISOPRQPY-LAMINE a RESIN COMPLEX so Tablet weigh t-2:00 mg.

.-nit. o-2. -d mc hy1.-l-phen l h ne was dissolved in Ta etsim-a/az absolute methanol, a the resin and the ca aly t we e The d ed 1W .ders are weighed. screened. and mlx ed.

added and hydrogenated. The reaction mixture was The mixture is granulated with the sucrose-starch paste, filtered and transferred to, sieve No. 60. It was then then through a. No. 8 screen and dried at 40 C. washed with cold water and dried. The dried granules are rescreened through a No. 14 screen and the lubricant is added. After final mixing,

EXAMPLE V the tablets are compressed to approximate gauge and Preparation of Beta-Phenyl-Alpha-Amino-Alpha Alphahardness.

Dimethyl Ethane 4a EXAMPLE v11 Fifteen parts of the above beta-phenyl-beta-chlorob alpha-aminoalpha-alpha-dimethyl ethane hydrochloride of I 180p mpylamme Base were dissolved in 150 parts of alcohol, and 5 parts of palladinized calcium carbonate added. The mixture was ffii'uigliifii' Formula ri ih then reduced in a conventional hydrogenation appa atus with hydrogen at -80 C. and under 50 lbs. pressure- I benzyl lsopropylaxnine Base 100 When hydrogen was no longer readily absorbed. the solua tion was removed, the palladinized calcium carbonate Polyvinylpyrolidone (as 25% solutl 75 filtered and the filtrate evaporated. The residue was dis- Magnesium steam solved in dilute hydrochloric acid, shaken with ether and the ether discarded. The acid solution was then made ggfgmii? alkaline, as with sodium hydroxide, and the amine extracted with ether. The other solution could (I) be dried The 1 benzyl sopwpyla'mme base absorbed on the and distilled to give the desired a-benzyl isopropyl amine, sufrch by q s P The f 1s ifdded f B.P. 205 at 750 mm. or 100 at 21 mm., or (2) the et er mlxedi f is granulated mm polyvmyflpywhsolution could be dried and saturated with hydrogen done solution; srzed through a No. l0 screen and dried at chloride and the precipitated hydrochloride recrystallized The dried granules are through a 14 from a mixture of 50 parts alcohol and 100 parts acetone. screen and the lubricant added .After final mixing the The pure hydrochloride was thus obtained as a white tablets are compressed to appmmam gauge and hard crystalline substance in yields of of the theoretical 60 Bess and having a MP. of 195-496 C. unc. EXAMPLE VH1 Other halogeno compounds could be used instead of Tablet of l-Benzyl-Isopropylamine Resin Complex the chloro compound.

Instead of palladinized calcium carbonate other hydro- PM Tablet, Fomura 10.0% genatlon catalysts may be used. Palladium and/or platlmilligrams grams nurn absorbed on a basic carrier such as an alkaline earth oxide or carbonate (especially calcium or magnesium) 30 lbenlyl isogwpyiamine as Resin 1.200 gives the best yield of the. substituted phenyl-ethane. 350 gfggff'f]: 3,500 Platinum and platinum oxidi'Adarns), alone, palladium g i 1? on charcoal, and Raney nickel may also be employed, but fiagag1g1 $ehr:a i 20 the yield of the beta-phenyl-alpha-alpha, dimethyl-alphaamino ethane compound is a smaller portion of the total Tablet weight-782 mg. product, while at the same time there is produced a substantial yield of the novel product, beta-cyclohcxyl' The resin complex is mixed with the starch and lactose,

alpha-alpha-dimethylalpha-amino ethane. By substitutand granulated with the polyvinylpyrolidone solution, then 7 passed through a No. 8 screen and dried at 40 C. The dried granules are sized through a No. 12 screen and the lubricant added. After final mixing, the tablets ar compressed to appropriate gauge and hardness.

EXAMPLE IX Capsules f I-Benzyl-Isopropylamine HOl The 1 benzyl isopropylamine base is absorbed on the starch by thorough mixing. The starch is then granulated with the polyvinylpyrolidone solution, and after screening through a 20 mesh screen, is dried at room temperature in circulating air. The dried granules are then sized through a 60 mesh screen and mixed with the magnesium stearate and dicalcium phosphate. After thorough mixing, the powder is filled into capsules.

EXAMPLE XI Capsules of I-Benzyl-Isopropylamine Resin Complex Per Capsule, Formula Per 10,000, milligrams grams 30 l benytyl lsopropylamlne resin complex 1,200

25 2.5 magne sium stearato 25 217.5 dlcalclum phosphate dihydrate 2, 175

Capsule slze#3 2-plece gelatin. Fill weight-250 mg.

The components are thoroughly mixed, then filled into capsules.

Up to the present time the products of choice employed by the medical profession for the suppression of appetite have been alpha-methylphenethyl amine (Amphetamine), desoxy ephedrine, 3-methyl-2-phenylmorpholine (Preludin). While these compositions have been satisfactory for the purpose, it has now been found that the resin complexes of alpha dissubstitnted ethane amines and salts, particularly when employed in pharmaceutical compositions in dosage form, are far superior to the known therapeutic compositions presently in use.

The specific examples refer to the use of Duolite 0-20 resin (a copolymer polystyrene type resin with a nuclear sulfonic acid functional group) as the cation exchange resin suitable for use in this invention. In addition to this resin, other sulfonic acid cation exchange resins may be employed.

The term "sulphonic acid cation exchange resin" is intended to include the phenol-sulphonic acid cation exchange resins and the carboxylic-sulphonic acid cation exchange resins. However, particularly satisfactory results have been obtained with the sulphonic acid cation exchange resins disclosed in the DAlelio Patent No. 2,366,007, such resins being sulphonated polymerizates of polyvinyl aryl compounds. These are cross-linked resins. Other suitable cross-linked cation exchange resins are disclosed in US. Patents Nos. 2,204,539; 2,228,159; and 2,729,607. Such resins are as follows:

lR-120.-A water insoluble sulphonated polymerizate of polyvinyl aryl compound made in accordance with Example I of US. Patent 2,633,007, except that 7.5 parts by weight of divlnyl benzene are used instead of 10 parts. The particle size is such that approximately of the particles are retained on a 40 mesh screen, 5.67% on a 20 mesh screen, and 3.33% on a 60 mesh screen. The product can be considered as substantially consisting of a particle size of between 20 and 40 mesh. The crosslinkage is between 7 and 8%.

XE-69.This is the same as lR-l20, except that substantially all particles pass through an 80 mesh screen and are retained on a 400 mesh screen. In general, all of these resins have been fully identified in the literature.

What is claimed is:

l. A therapeutically effective appetite suppressing and mood elevating composition having reduced side effects, in dosage unit form, adapted for the treatment of obesity, comprising a pharmaceutical carrier and from 2 to milligrams per dosage unit of a medicament having the formula where Y represents a saturated carbocyelic five-membered ring and Z represents a sulfonic acid cation exchange resin forming a resin complex with the base.

2. The method of treating an obese patient to effect a suppression of appetite which comprises orally admin istering to said patient the composition of claim 1.

References Cited in the file of this patent UNITED STATES PATENTS 2,189,570 Schechter Feb. 6, 1940 2,408,345 Shelton Sept. 24, 1946 2,498,687 Larsen Feb. 28, 1950 2,673,223 Wood Mar. 23, 1954 2,673,827 Kohlstaedt Mar. 30, 1954 2,677,670 Kunim May 4, 1954 2,697,059 Gustus Dec. 14, 1954 2,794,786 Segal June 4, 1957 2,837,578 Brown June 3, 1958 2,990,332 Keating June 27, 1961 OTHER REFERENCES Freed: Annals of Int. Med., vol. 44, 1956, pp. ll36 1141. 

1. A THERAPEUTICALLY EFFECTIVE APPETITE SUPPRESSING AND MOOD ELEVATING COMPOSITION HAVING REDUCED SIDE EFFECTS, IN DOSAGE UNIT FROM, ADAPTED FOR THE TREATMENT OF OBESITY, COMPRISING A PHARMCAEUTICAL CARRIER AND FROM 2 TO 150 MILLIGRAMS PER DOSAGE UNIT OF A MEDICAMENT HAVING THE FORMULA 